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1. Benefit of Mineralocorticoid Receptor Antagonism in AKI: Role of Vascular Smooth Muscle Rac1

Author

Jonatan Barrera-Chimal, Sonia Prince, Peter Kolkhof, Sebastian M. Lechner, Gwennan André-Grégoire, Vincent Sauzeau, Frederic Jaisser, Jerome Cau, Gervaise Loirand, Thierry Hauet, Aurelie Nguyen Dinh Cat, Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques ( IRTOMIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Poitiers - Faculté de Médecine et de Pharmacie, Université de Poitiers, Fédération Hospitalo-universitaire SUrvival oPtimization in ORgan Transplantation (FHU SUPORT), Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)-Anti-infectieux : supports moléculaires des résistances et innovations thérapeutiques (RESINFIT), CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Ciblage individuel et prévention des risques de traitements immunosupresseurs et de la transplantation (IPPRITT), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Institut National de la Santé et de la Recherche Médicale (INSERM)- Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques ( IRTOMIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers-Cellules Dendritiques, Immunomodulation et Greffes, Université de Tours-Université de Tours, UE1372 GENESI, IBiSA Plateforme MOPICT, Institut National de la Recherche Agronomique (INRA), Service de Biochimie, French-Clinical Research Infrastructure Network [Lyon] (FCRIN INI-CRCT - Coordination Nationale Réseau FORCE), Centre de Recherche en Nutrition Humaine Rhône-Alpes (CRNH-RH), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-CHU Saint-Etienne-Hospices Civils de Lyon (HCL)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-CHU Saint-Etienne-Hospices Civils de Lyon (HCL)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de recherche de l'institut du thorax (ITX-lab), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM)-Anti-infectieux : supports moléculaires des résistances et innovations thérapeutiques (RESINFIT), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Cellules Dendritiques, Immunomodulation et Greffes, Université de Tours (UT)-Université de Tours (UT)-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Ciblage individuel et prévention des risques de traitements immunosupresseurs et de la transplantation (IPPRITT), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique, Expérimentation et Système Innovants (GenESI), Centre de Recherche en Nutrition Humaine Rhône-Alpes (CRNH-RA), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), ANR-16-CE14-0021,RENOMIR,Bénéfice de l'antagonisme du récepteur minéralocorticoïde en pathologie rénale: mécanismes et implications thérapeutiques(2016), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Anti-infectieux : supports moléculaires des résistances et innovations thérapeutiques (RESINFIT), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM)-Cellules Dendritiques, Immunomodulation et Greffes, Université de Tours (UT)-Université de Tours (UT), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-CHU Saint-Etienne-Hospices Civils de Lyon (HCL)-CHU Grenoble, CHU Limoges-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM)- Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques ( IRTOMIT), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), and Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-CHU Limoges-Ciblage individuel et prévention des risques de traitements immunosupresseurs et de la transplantation (IPPRITT)

Subjects
0301 basic medicine, rac1 GTP-Binding Protein, Male, Vascular smooth muscle, Swine, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, urologic and male genital diseases, Muscle, Smooth, Vascular, ischemia-reperfusion, Mice, 0302 clinical medicine, Mineralocorticoid receptor, vascular, Smooth Muscle, Myocyte, Aldosterone, Cells, Cultured, Mineralocorticoid Receptor Antagonists, Kidney, NADPH oxidase, Cultured, biology, Acute kidney injury, General Medicine, Acute Kidney Injury, female genital diseases and pregnancy complications, 3. Good health, medicine.anatomical_structure, Nephrology, Reperfusion Injury, Muscle, Smooth, medicine.medical_specialty, Finerenone, Cells, Myocytes, Smooth Muscle, 03 medical and health sciences, Internal medicine, medicine, Animals, Myocytes, business.industry, urogenital system, Neuropeptides, medicine.disease, Basic Research, 030104 developmental biology, Endocrinology, Oxidative stress, biology.protein, business, Reperfusion injury
Abstract

International audience; AKI is a frequent complication in hospitalized patients. Unfortunately, there is no effective pharmacologic approach for treating or preventing AKI. In rodents, mineralocorticoid receptor (MR) antagonism prevents AKI induced by ischemia-reperfusion (IR). We investigated the specific role of vascular MR in mediating AKI induced by IR. We also assessed the protective effect of MR antagonism in IR-induced AKI in the Large White pig, a model of human AKI. In mice, MR deficiency in smooth muscle cells (SMCs) protected against kidney IR injury. MR blockade by the novel nonsteroidal MR antagonist, finerenone, or genetic deletion of MR in SMCs associated with weaker oxidative stress production. Moreover, ischemic kidneys had higher levels of Rac1-GTP, required for NADPH oxidase activation, than sham control kidneys, and genetic deletion of Rac1 in SMCs protected against AKI. Furthermore, genetic deletion of MR in SMCs blunted the production of Rac1-GTP after IR. Pharmacologic inhibition of MR also prevented AKI induced by IR in the Large White pig. Altogether, we show that MR antagonism, or deletion of the MR gene in SMCs, limited the renal injury induced by IR through effects on Rac1-mediated MR signaling. The benefits of MR antagonism in the pig provide a rational basis for future clinical trials assessing the benefits of this approach in patients with IR-mediated AKI.

Published
2017

2. Inhibition of coagulation proteases Xa and IIa decreases ischemia-reperfusion injuries in a preclinical renal transplantation model

Author

Sandrine Joffrion, Thomas Kerforne, Jean-Michel Goujon, Jerome Cau, Maurice Petitou, Solenne Tillet, Gérard Mauco, Thierry Hauet, T. Saintyves, Sébastien Giraud, Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques ( IRTOMIT), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Biochimie [Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Département d'Anesthésie et Réanimation Chirurgicale [Poitiers], Service d'Urologie [Poitiers], Service de Chirurgie Urologie [Angoulême], Centre hospitalier d'Angoulême, Service d’Anapathomopathologie [Poitiers], IBiSA Plateforme, Plate-forme MOdélisation Préclinique - Innovation Chirurgicale et Technologique (MOPICT), Institut National de la Recherche Agronomique (INRA), Fédération Hospitalo-universitaire SUrvival oPtimization in ORgan Transplantation (FHU SUPORT), Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Anti-infectieux : supports moléculaires des résistances et innovations thérapeutiques (RESINFIT), CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Ciblage individuel et prévention des risques de traitements immunosupresseurs et de la transplantation (IPPRITT), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Institut National de la Santé et de la Recherche Médicale (INSERM)- Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques ( IRTOMIT), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM)-Cellules Dendritiques, Immunomodulation et Greffes, Université de Tours (UT)-Université de Tours (UT), This work was supported by institutional grants from Inserm, Conseil Régional Poitou-Charentes, Université de Poitiers and CHU de Poitiers. S.T. received a PhD grant from the Fondation de Transplantation and the Société Francophone de Transplantation., Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM)-Anti-infectieux : supports moléculaires des résistances et innovations thérapeutiques (RESINFIT), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Cellules Dendritiques, Immunomodulation et Greffes, Université de Tours (UT)-Université de Tours (UT)-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Ciblage individuel et prévention des risques de traitements immunosupresseurs et de la transplantation (IPPRITT), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Dupuis, Christine, Département d’Anesthésie-Réanimation, Université de Poitiers - Faculté de Médecine et de Pharmacie, Université de Poitiers, Service d’Anapathomopathologie, ENDOTIS PHARMA, Partenaires INRAE, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers, Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)-Anti-infectieux : supports moléculaires des résistances et innovations thérapeutiques (RESINFIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers-Cellules Dendritiques, Immunomodulation et Greffes, and Université de Tours-Université de Tours

Subjects
0301 basic medicine, Sus scrofa, Oligosaccharides, Pharmacology, Kidney, Kidney Function Tests, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, chemistry.chemical_compound, Leukocytes, Hypoxia, Cell adhesion molecule, Thrombin, General Medicine, 3. Good health, Cold Temperature, medicine.anatomical_structure, Reperfusion Injury, Factor Xa, Models, Animal, Prothrombin, Epithelial-Mesenchymal Transition, Ischemia, Biotin, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, 03 medical and health sciences, Tissue factor, Physiology (medical), medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, Viaspan, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, VCAM-1, Blood Coagulation, Inflammation, business.industry, Biochemistry (medical), Public Health, Environmental and Occupational Health, Endothelial Cells, medicine.disease, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Fibrosis, Kidney Transplantation, Transplantation, 030104 developmental biology, chemistry, Immunology, business, Reperfusion injury, Biomarkers, Factor Xa Inhibitors
Abstract

Coagulation is an important pathway in the pathophysiology of ischemia-reperfusion injuries. In particular, deceased after circulatory death (DCD) donors undergo a no-flow period, a strong activator of coagulation. Hence, therapies influencing the coagulation cascade must be developed. We evaluated the effect of a new highly specific and effective anti-Xa/Ila molecule, with an integrated innovative antidote site (EP217609), in a porcine preclinical model mimicking injuries observed in DCD donor kidney transplantation. Kidneys were clamped for 60 minutes (warm ischemia), then flushed and preserved for 24 hours at 4 degrees C in University of Wisconsin (UW) solution (supplemented or not). EP217609-supplemented UW solution (UW-EP), compared with unfractionated heparin-supplemented UW solution (UW-UFH) or UW alone (UW). A mechanistic investigation was conducted in vitro: addition of EP217609 to endothelial cells during hypoxia at 4 degrees C in the UW solution inhibited thrombin generation during reoxygenation at 37 degrees C in human plasma and reduced tumor necrosis factor alpha, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 messenger RNA cell expressions. In vivo, function recovery was markedly improved in the UW-EP group. Interestingly, levels of thrombin-anti thrombin complexes (reflecting thrombin generation) were reduced 60 minutes after reperfusion in the UW-EP group. In addition, 3 months after transplantation, lower fibrosis, epithelial-mesenchymal transition, inflammation, and leukocyte infiltration were observed. Using this new dual anticoagulant, anti-Xa/lla activity during kidney flush and preservation is protected by reducing thrombin generation at revascularization, improving early function recovery, and decreasing chronic lesions. Such an easy-to-deploy clinical strategy could improve marginal graft outcome.

Published
2015

3. Modulation of Peripheral-Type Benzodiazepine Receptor During Ischemia Reperfusion Injury in a Pig Kidney Model: A New Partner of Leukemia Inhibitory Factor in Tubular Regeneration

Author

Keqiang Zhang, Gérard Mauco, Michel Carretier, Jerome Cau, Frédéric Favreau, Vassilios Papadopoulos, Jean Michel Goujon, Thibault Desurmont, Thierry Hauet, and Séverine Deretz

Subjects
Male, medicine.medical_specialty, Proliferation index, Swine, Ischemia, Kidney, Leukemia Inhibitory Factor, Internal medicine, medicine, Animals, Regeneration, RNA, Messenger, Receptor, Messenger RNA, Interleukin-6, business.industry, Proteins, Receptors, GABA-A, medicine.disease, Kidney Tubules, medicine.anatomical_structure, Endocrinology, Mitochondrial permeability transition pore, Reperfusion Injury, Surgery, business, Reperfusion injury, Leukemia inhibitory factor
Abstract

Background It was demonstrated that postischemic kidney expresses different factors in a pattern that recapitulates expression of these factors in the developing kidney. We investigated whether peripheral-type benzodiazepine receptor (PBR), which belongs to the mitochondrial permeability transition pore and is essential during development, could be influenced by the ischemia-reperfusion injury process when compared with leukemia inhibitor factor (LIF). Study design PBR, LIF, and LIF receptor messengers and proteins were analyzed in adult normal and ischemic kidney under conditions mimicking cardiac arrest: 18 pigs were studied after 60 minutes of warm ischemia and reperfusion for 7 days and compared with sham-operated (Sham, n=12) and control (CONT, n=12) groups. The same messengers and proteins were assessed in fetal kidneys. Results In normal kidney, PBR was expressed in descending and ascending limbs of Henle and in distal tubules. After ischemia-reperfusion injury, PBR mRNA significantly increased between days 1 and 7 in cortex and outer medulla. PBR protein increased between days 1 and 7, and was transiently expressed in proximal tubules at days 1 and 3 and returned to basal level at day 7. LIF messenger and protein increased rapidly at day 1 in proximal tubules. In turn, LIF receptor messenger and protein were not changed during reperfusion. Conclusions These results suggest that PBR may be implicated in ischemia-reperfusion injury and, particularly, in the regenerative process within proximal tubules with LIF. These new insights open the possibility of novel targets for organ protection and repair.

Published
2006

4. Evaluation of Early Regenerative Processes in a Preclinical Pig Model of Acute Kidney Injury

Author

R. Robert, Julie Demars, Ludivine Rossard, Frédéric Favreau, Cedric Nadeau, R. Thuillier, Thierry Hauet, Jerome Cau, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Poitiers, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Laboratoire de Génétique Cellulaire (LGC), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, IBISA, IBiSA, Ischémie - Reperfusion en transplatation rénale, Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Conseil Regional Poitou-Charentes, Fondation Centaure (Reseau de recherche en transplantation), French Society of Organ Transplantation, and Banque Tarneaud (Poitiers)

Subjects
Pathology, Cell division, Swine, [SDV]Life Sciences [q-bio], Gene Expression, PROTEIN, ISCHEMIA-REPERFUSION INJURY, BENZODIAZEPINE-RECEPTOR, 030230 surgery, Kidney, Biochemistry, 0302 clinical medicine, repair process, ischemia reperfusion injury, 0303 health sciences, biology, CHOLESTEROL, Acute kidney injury, General Medicine, Cell cycle, RECOVERY, STATHMIN, Cold Temperature, medicine.anatomical_structure, Reperfusion Injury, Molecular Medicine, Cholesterol Esters, Glomerular Filtration Rate, medicine.medical_specialty, PARTNERS, RENAL-FAILURE, Ischemia, Cold storage, Stathmin, 03 medical and health sciences, Receptors, GABA, Internal medicine, Proliferating Cell Nuclear Antigen, medicine, Animals, Regeneration, MODULATION, Molecular Biology, 030304 developmental biology, business.industry, hypoxia, TRANSPLANTATION, medicine.disease, Kidney Transplantation, Proliferating cell nuclear antigen, Endocrinology, biology.protein, business
Abstract

International audience; Renal failure due to ischemic injury is a common denominator of various clinical situations in critically ill patients. This study was designed to characterize the TPSO/Cholesterol synthesis and cell division pathways in response to different levels of ischemia. Porcine kidneys were subjected to either 60min-warm ischemia (WI) or auto-transplanted after cold storage for 24h at 4 degrees C (CS), or both conditions (WI+ CS), pathway activation and function were evaluated at 3h, 3 and 7 days after reperfusion. CS combined to WI affects renal functions indicating a high degree of injury. During the first week of reperfusion, renal levels of free and esterified cholesterol, major cellular components, increased in CS group with an attenuated production when WI was associated. CS and WI+ CS groups exhibited an elevated expression of cell cycle induction markers such as PCNA and stathmin. TSPO expression was highest in groups with the lowest injury, and correlated with kidney outcome, revealing its potential for diagnosis.

Published
2012

5. Anti-thrombin therapy during warm ischemia and cold preservation prevents chronic kidney graft fibrosis in a DCD model

Author

Thierry Hauet, Xiangyang Zhu, R. Thuillier, S. Milin, Frédéric Favreau, Lilach O. Lerman, Gérard Mauco, Emilie Manguy, Jerome Cau, Ischémie - Reperfusion en transplatation rénale, Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Médecine et de Pharmacie, Université officielle de Bukavu, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Division of Nephrology and Hypertension, Mayo Clinic, Génétique Expérimentale en Productions Animales (GEPA), Institut National de la Recherche Agronomique (INRA), ProdInra, Migration, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers

Subjects
Male, [SDV.SA]Life Sciences [q-bio]/Agricultural sciences, Benzylamines, Pathology, Adenosine, [SDV.MHEP.CHI] Life Sciences [q-bio]/Human health and pathology/Surgery, Swine, 030232 urology & nephrology, 030230 surgery, Kidney, Peritubular capillaries, chemistry.chemical_compound, 0302 clinical medicine, Transforming Growth Factor beta, Fibrosis, Insulin, Immunology and Allergy, Pharmacology (medical), direct thrombin inhibitor, ischemia reperfusion injury, [SDV.SA] Life Sciences [q-bio]/Agricultural sciences, Temperature, Organ Preservation, Glutathione, Tissue Donors, 3. Good health, medicine.anatomical_structure, Tissue Plasminogen Activator, Models, Animal, Signal Transduction, kidney preservation, medicine.medical_specialty, Allopurinol, Organ Preservation Solutions, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, Transplantation, Autologous, Article, 03 medical and health sciences, Raffinose, interstitial fibrosis/tubular atrophy, Plasminogen Activator Inhibitor 1, medicine, Renal fibrosis, Animals, Humans, RNA, Messenger, Sirius Red, DNA Primers, Transplantation, Base Sequence, business.industry, graft function, Anticoagulants, Kidney metabolism, medicine.disease, Kidney Transplantation, CTGF, Oxidative Stress, chemistry, Chronic Disease, Azetidines, business, Reperfusion injury
Abstract

International audience; Ischemia reperfusion injury (IRI) is pivotal for renal fibrosis development via peritubular capillaries injury. Coagulation represents a key mechanism involved in this process. Melagatran (R) (M), a thrombin inhibitor, was evaluated in an autotransplanted kidney model, using Large White pigs. To mimic deceased after cardiac death donor conditions, kidneys underwent warm ischemia (WI) for 60 min before cold preservation for 24 h in University of Wisconsin solution. Treatment with M before WI and/or in the preservation solution drastically improved survival at 3 months, reduced renal dysfunction related to a critical reduction in interstitial fibrosis, measured by Sirius Red staining. Tissue analysis revealed reduced expression of transforming growth factor-beta (TGF-beta) and activation level of its effectors phospho-Smad3, Smad4 and connective tissue growth factor (CTGF) after M treatment. Fibrinolysis activation was also observed, evidenced by downregulation of PAI-1 protein and gene expression. In addition, M reduced S100A4 expression and vimentin staining, which are markers for epithelial mesenchymal transition, a major pathway to chronic kidney fibrosis. Finally, expression of oxidative stress markers Nox2 and iNOS was reduced. We conclude that inhibition of thrombin is an effective therapy against IRI that reduces chronic graft fibrosis, with a significantly positive effect on survival.

Published
2010

6. Influence of warm ischemia time on peripheral-type benzodiazepine receptor: A new aspect of the role of mitochondria

Author

Jerome Cau, Guillaume Febrer, Jean-Pierre Richer, William Hebrard, Keqiang Zhang, M. Scepi, Christophe Burucoa, Thibault Desurmont, Vassilios Papadopoulos, Cedric Nadeau, Thierry Hauet, Jean Michel Goujon, Pierre Leyre, Michel Carretier, Carole Doucet, ProdInra, Migration, Génétique Expérimentale en Productions Animales (GEPA), and Institut National de la Recherche Agronomique (INRA)

Subjects
Male, Pathology, Magnetic Resonance Spectroscopy, Time Factors, Swine, Physiology, [SDV]Life Sciences [q-bio], Mitochondrion, 0302 clinical medicine, MITOCHONDRIA, PIGS, Warm Ischemia, Receptor, ComputingMilieux_MISCELLANEOUS, Kidney Medulla, 0303 health sciences, Warm Ischemia Time, Reverse Transcriptase Polymerase Chain Reaction, General Medicine, SURGEON, Immunohistochemistry, Peripheral, Cell biology, ISCHEMIA, [SDV] Life Sciences [q-bio], Nephrology, Reperfusion Injury, 030220 oncology & carcinogenesis, medicine.symptom, medicine.medical_specialty, medicine.drug_class, Blotting, Western, Lesion, Methylamines, 03 medical and health sciences, KIDNEY, Receptors, GABA, Peripheral-Type Benzodiazepine Receptor, Genetics, medicine, Animals, RNA, Messenger, 030304 developmental biology, Benzodiazepine, business.industry, medicine.disease, Survival Analysis, Reperfusion, business, Reperfusion injury
Abstract

The peripheral benzodiazepine receptor (PBR) is located mainly in the outer mitochondrial membrane and many functions are associated directly or indirectly with the PBR. We have studied the influence of different durations of warm ischemia (WI) on renal function, tissue damage and PBR expression in a Large Whitepig model. After a midline incision, the renal pedicle was clamped for 10 (WI10), 30 (WI30), 45 (WI45), 60 (WI60) or 90 min (WI90), and blood and renal tissue samples were collected between 1 day and 2 weeks after reperfusion for assessment of renal function. Metabolite excretion associated with renal ischemia reperfusion injury such as trimethylamine-N-oxide (TMAO) was quantified in blood by magnetic resonance spectroscopy. PBR mRNA and protein expression were determined in renal tissue. TMAO levels rose progressively and significantly with increasing duration of WI. PBR mRNA expression was upregulated between 3 h and 1 day after reperfusion in WI30, WI45 and WI60. Its upregulation was noted 3 days after reperfusion in WI90. At day 14, PBR transcript expression was not different from basal level in any group. PBR protein followed the same pattern. These findings suggest a new role for PBR which could be a major target in the regeneration process during ischemia reperfusion.

Published
2007

7. In Vitro/Ex Vivo Models for the Study of Ischemia Reperfusion Injury during Kidney Perfusion

Author

Sebastien Giraud, Raphaël Thuillier, Jérome Cau, and Thierry Hauet

Subjects
kidney, in vitro, oxidative stress, perfusion, oxygenation, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Oxidative stress is a key element of ischemia–reperfusion injury, occurring during kidney preservation and transplantation. Current options for kidney graft preservation prior to transplantation are static cold storage (CS) and hypothermic machine perfusion (HMP), the latter demonstrating clear improvement of preservation quality, particularly for marginal donors, such as extended criteria donors (ECDs) and donation after circulatory death (DCDs). Nevertheless, complications still exist, fostering the need to improve kidney preservation. This review highlights the most promising avenues of in kidney perfusion improvement on two critical aspects: ex vivo and in vitro evaluation.

Published
2020
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8. FR167653 improves renal recovery and decreases inflammation and fibrosis after renal ischemia reperfusion injury

Author

Jerome Cau, Gilles Regnault de la Motte, Jean-Baptiste Ricco, Jean-Michel Goujon, Thierry Hauet, Guillaume Febrer, Keqiang Zhang, and Frédéric Favreau

Subjects
Male, Pathology, medicine.medical_specialty, Necrosis, Time Factors, Pyridines, Swine, medicine.medical_treatment, Urology, Renal function, Kidney, Kidney Function Tests, Nephrectomy, p38 Mitogen-Activated Protein Kinases, Fibrosis, medicine, Renal fibrosis, Animals, Renal Insufficiency, Warm Ischemia, Phosphorylation, Infusions, Intravenous, Acute tubular necrosis, Inflammation, Renal ischemia, business.industry, Tumor Necrosis Factor-alpha, Anti-Inflammatory Agents, Non-Steroidal, Recovery of Function, medicine.disease, Constriction, Disease Models, Animal, Proteinuria, Reperfusion Injury, Pyrazoles, Surgery, medicine.symptom, Cardiology and Cardiovascular Medicine, business, Kidney disease, Interleukin-1
Abstract

ObjectiveAcute tubular necrosis (ATN) secondary to induced warm ischemia (WI) results in inflammatory and delayed fibrotic processes and remains a common clinical problem with serious consequences. Because tumor necrosis factor-α (TNF-α) is a prominent proinflammatory factor implicated in the pathophysiology of acute renal ischemia reperfusion injury (IRI), we hypothesized that FR167653 (FR), a potent inhibitor of TNF-α and interleukin-1β production, may reduce IRI.MethodsIRI was induced in male pigs by bilateral clamping of the renal pedicle for 90 minutes (WI90), or unilateral renal clamping (90 minutes) after contralateral nephrectomy (1/2N×90), or unilateral renal clamping without contralateral nephrectomy (WIuni90). FR was administered intravenously 60 minutes before WI (1 mg/kg/h), during WI, and continuously for 3 hours (1 mg/kg/h) during reperfusion in treated groups (FRWI90, FR1/2N×90, or FRWIuni90). Blood and urine samples were collected between day 1 and 3 months after reperfusion for assessment of renal function. Kidneys were excised and renal tissues were collected at 3 months for morphologic and inflammation evaluation and protein analysis. Experimental groups were compared with sham operated (control) and heminephrectomized (Unif) groups without renal ischemia.ResultsThree WI90 animals (43%) and five 1/2N×90 (70%) were euthanized and necropsied at day 7 because of no urine production or poor conditions. Mortality was significantly improved after FR treatment. Survival was 100% in the control, Unif, WIuni90, and FR groups. In Unif groups, FR significantly reduced renal failure and bilateral renal ischemia (P < .05). At 3 months, proteinuria was significantly reduced in FR-treated groups (P < .01). Inflammatory cells count was also dramatically diminished in FR-treated pigs (P < .01 for CD3-positive cells). The second aspect of transient ischemia is the fibrotic process determined at 3 months. FR treatment was characterized by a reduction of renal fibrosis, particularly in Unif groups. TNF-α protein expression was diminished in FR-treated groups.ConclusionThis is the first evidence that FR reduced the early and long-term effect of WI in the severe ischemia model. This effect was particularly marked against fibrosis and inflammation, which would contribute to deterioration of a patient's renal function.Clinical RelevanceAcute ischemia of the kidney is common in the setting of renal artery or aortic surgery. Deterioration in renal function is a common cause of morbidity in patients treated surgically for juxtarenal and suprarenal abdominal aortic aneurysms. FR167653 represents a useful therapeutic approach to prevent renal damage in a planned period of warm ischemia and during suprarenal aortic surgery.

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9. Trimetazidine reduces early and long-term effects of experimental renal warm ischemia: A dose effect study

Author

Frédéric Favreau, Thierry Hauet, Jean Paul Tillement, Jean Michel Goujon, Lilach O. Lerman, and Jerome Cau

Subjects
medicine.medical_specialty, Pathology, Swine, Vasodilator Agents, Blotting, Western, Trimetazidine, Urology, Renal function, Apoptosis, Inflammation, Kidney, Nephrectomy, Renal Circulation, Fibrosis, medicine, Animals, Vimentin, Warm Ischemia, Tissue Survival, Dose-Response Relationship, Drug, business.industry, Hypoxia (medical), Hypoxia-Inducible Factor 1, alpha Subunit, medicine.disease, Immunohistochemistry, medicine.anatomical_structure, Reperfusion Injury, Surgery, medicine.symptom, business, Cardiology and Cardiovascular Medicine, Myofibroblast, medicine.drug
Abstract

ObjectiveRenal ischemia reperfusion (IR) injury (IRI) is an important mechanism of acute renal failure (ARF) and a crucial factor of tissue damage during vascular surgery. IR may lead to tissue destruction and influence the early and long-term outcome of organs. The anti-anginal medication trimetazidine (TMZ) is a drug, the protective effects of which have been already assessed during cold preservation and warm ischemia (WI). The objective of this dose-effect study was to assess the role of TMZ in severe renal WI model.Materials and MethodsWe have used an established WI pig kidney model associated with a uninephrectomy condition and studied the dose-dependent role of TMZ (1, 5, and 10 mg/Kg, i.v. for 24 hours before WI) against deleterious effects of WI (60 minutes of WI followed by reperfusion) compared with sham-operated (control) and uninephrectomized animals (unif). Direct effect of TMZ was determined using different variables: renal function (creatinine clearance; Ccr) and indirectly, the consequences on inflammation (cells infiltration), rate of apoptosis, fibrosis development, and renal epithelial cells change into myofibroblast, which defined epithelial to mesenchymal transition (α-smooth muscle actin [α-SMA] and vimentin expression).ResultsTMZ (5 or 10 mg/Kg) significantly increased Ccr and reduced the inflammatory response prevalent in ischemic kidney injury and rate of apoptosis expression. In addition, the limitation of initial IRI was correlated with an earlier and greater expression of hypoxia-inducible transcription factor-1α (HIF-1α), which is a hypoxia marker during kidney regeneration. A reduction of the tubulointerstitial development of fibrosis and a limitation of the α-smooth muscle actin expression (α-SMA) was observed with TMZ treatment. At 3 months, vimentin expression was increased in WI groups without TMZ or low TMZ dose treatment compared with 5 or 10 mg/Kg treated groups.ConclusionCollectively, these data suggest that TMZ made the warm ischemic kidneys more resistant to the deleterious impact of a single episode of IR and could have a role in preserving the ischemic kidney from long-term damage.Clinical RelevanceOur results suggest that TMZ limits in a dose-dependent manner IRI after 60 minutes of WI. This drug could be useful to prevent deleterious consequences of renal ischemia accompanied by a nephronic mass reduction (which mimic clinical situation of patients with chronic nephropathy who are at risk for vascular diseases), during thoracoabdominal aortic surgery, or operations with a planned period of WI (renal artery by-pass, juxta or supra-renal and thoracoabdominal aneurysm repair and promote renal recovery in a preclinical model.

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